Method for inhibiting bone resorption

ABSTRACT

Disclosed are methods for inhibiting bone resorption in mammals while minimizing the occurrence of or potential for adverse gastrointestinal effects. Also disclosed are pharmaceutical compositions and kits for carrying out the therapeutic methods disclosed herein.

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application is a continuation of PCT/US98/14796, filed Jul.17, 1998, and also claims priority to U.S. provisional applications Ser.No. 60/053,535, filed Jul. 23, 1997, and No. 60/053,351, filed Jul. 22,1997, both now abandoned, the contents of all of the foregoing of whichare hereby incorporated by reference in their entirety.

FIELD OF THE INVENTION

[0002] The present invention relates to oral methods for inhibiting boneresorption in a mammal while minimizing the occurrence of or potentialfor adverse gastrointestinal effects. These methods comprise orallyadministering to a mammal in need thereof of a pharmaceuticallyeffective amount of a bisphosphonate as a unit dosage according to acontinuous schedule having a dosing interval selected from the groupconsisting of once-weekly dosing, twice-weekly dosing, biweekly dosing,and twice-monthly dosing. The present invention also relates topharmaceutical compositions and kits useful for carrying out thesemethods.

BACKGROUND OF THE INVENTION

[0003] A variety of disorders in humans and other mammals involve or areassociated with abnormal bone resorption. Such disorders include, butare not limited to, osteoporosis, Paget's disease, periprosthetic boneloss or osteolysis, and hypercalcemia of malignancy. The most common ofthese disorders is osteoporosis, which in its most frequentmanifestation occurs in postmenopausal women. Osteoporosis is a systemicskeletal disease characterized by a low bone mass and microarchitecturaldeterioration of bone tissue, with a consequent increase in bonefragility and susceptibility to fracture. Because osteoporosis, as wellas other disorders associated with bone loss, are chronic conditions, itis believed that appropriate therapy will generally require chronictreatment.

[0004] Multinucleated cells called osteoclasts are responsible forcausing bone loss through a process known as bone resorption. It is wellknown that bisphosphonates are selective inhibitors of osteoclastic boneresorption, making these compounds important therapeutic agents in thetreatment or prevention of a variety of generalized or localized bonedisorders caused by or associated with abnormal bone resorption. See H.Fleisch, Bisphosphonates In Bone Disease, From The Laboratory To ThePatient, 2nd Edition, Parthenon Publishing (1995), which is incorporatedby reference herein in its entirety.

[0005] At present, a great amount of preclinical and clinical dataexists for the potent bisphosphonate compound alendronate. Evidencesuggests that other bisphosphonates such as risedronate, tiludronate,ibandronate and zolendronate, have many properties in common withalendronate, including high potency as inhibitors of osteoclastic boneresorption. An older bisphosphonate compound, etidronate, also inhibitsbone resorption. However, unlike the more potent bisphosphonates,etidronate impairs mineralization at doses used clinically, and may giverise to osteomalacia, a condition resulting in an undesirable decreasein bone mineralization. See Boyce, B. F., Fogelman, I., Ralston, S. etal. (1984) Lancet 1(8381), pp. 821-824 (1984), and Gibbs, C. J., Aaron,J. E.; Peacock, M. (1986) Br. Med. J. 292, pp. 1227-1229 (1986), both ofwhich are incorporated by reference herein in their entirety.

[0006] Despite their therapeutic benefits, bisphosphonates are poorlyabsorbed from the gastrointestinal tract. See B. J. Gertz et al.,Clinical Pharmacology of Alendronate Sodium, Osteoporosis Int., Suppl.3: S13-16 (1993) and B. J. Gertz et al., Studies of the oralbioavailability of alendronate, Clinical Pharmacology & Therapeutics,vol. 58, number 3, pp. 288-298 (September 1995), which are incorporatedby reference herein in their entirety. Intravenous administration hasbeen used to overcome this bioavailability problem. However, intravenousadministration is costly and inconvenient, especially when the patientmust be given an intravenous infusion lasting several hours on repeatedoccasions.

[0007] If oral administration of the bisphosphonate is desired,relatively high doses must be administered to compensate for the lowbioavailability from the gastrointestinal tract. To offset this lowbioavailability, it is generally recommended that the patient take thebisphosphonate on an empty stomach and fast for at least 30 minutesafterwards. However, many patients find the need for such fasting on adaily basis to be inconvenient. Moreover, oral administration has beenassociated with adverse gastrointestinal effects, especially thoserelating to the esophagus. See Fleisch, Id. These effects appear to berelated to the irritant potential of the bisphosphonate in theesophagus, a problem which is exacerbated by the presence of refluxedgastric acid. For example, the bisphosphonate, pamidronate has beenassociated with esophageal ulcers. See E. G. Lufkin et al., Pamidronate:An Unrecognized Problem in Gastrointestinal Tolerability, OsteoporosisInternational, 4: 320-322 (1994), which is incorporated by referenceherein in its entirety. Although not as common, the use of alendronatehas been associated with esophagitis and/or esophageal ulcers. See P. C.De Groen, et al., Esophagitis Associated With The Use Of Alendronate,New England Journal of Medicine, vol. 335, no. 124, pp. 1016-1021(1996), D. O. Castell, Pill Esophagitis—The Case of Alendronate, NewEngland Journal of Medicine, vol. 335, no. 124, pp. 1058-1059 (1996),and U. A. Liberman et al., Esophagitis and Alendronate, New EnglandJournal of Medicine, vol. 335, no. 124, pp. 1069-1070 (1996), which areincorporated by reference herein in their entirety. The degree ofadverse gastrointestinal effects of bisphosphonates has been shown toincrease with increasing dose. See C. H. Chestnut et al., AlendronateTreatment of the Postmenopausal Osteoporotic Woman: Effect of MultipleDosages on Bone Mass and Bone Remodeling, The American Journal ofMedicine, vol. 99, pp. 144-152, (August 1995), which is incorporated byreference herein in its entirety. Also, these adverse esophageal effectsappear to be more prevalent in patients who do not take thebisphosphonate with an adequate amount of liquid or who lie down shortlyafter dosing, thereby increasing the chance for esophageal reflux.

[0008] Current oral bisphosphonate therapies generally fall into twocategories: (1) those therapies utilizing continuous daily treatment,and (2) those therapies utilizing a cyclic regimen of treatment and restperiods.

[0009] The continuous daily treatment regimens normally involve thechronic administration of relatively low doses of the bisphosphonatecompound, with the objective of delivering the desired cumulativetherapeutic dose over the course of the treatment period. However,continuous daily dosing has the potential disadvantage of causingadverse gastrointestinal effects due to the repetitive, continuous, andadditive irritation to the gastrointestinal tract. Also, becausebisphosphonates should be taken on an empty stomach followed by fastingand maintenance of an upright posture for at least 30 minutes, manypatients find daily dosing to be burdensome. These factors can thereforeinterfere with patient compliance, and in severe cases even requirecessation of treatment.

[0010] Cyclic treatment regimens were developed because somebisphosphonates, such as etidronate, when given daily for more thanseveral days, have the disadvantage of actually causing a decline inbone mineralization, i.e. osteomalacia. U.S. Pat. No. 4,761,406, toFlora et al, issued Aug. 2, 1988, which is incorporated by referenceherein in its entirety, describes a cyclic regimen developed in anattempt to minimize the decline in bone mineralization while stillproviding a therapeutic anti-resorptive effect. Generally, cyclicregimens are characterized as being intermittent, as opposed tocontinuous treatment regimens, and have both treatment periods duringwhich the bisphosphonate is administered and nontreatment periods topermit the systemic level of the bisphosphonate to return to baseline.However, the cyclic regimens, relative to continuous dosing, appear toresult in a decreased therapeutic antiresorptive efficacy. Data onrisedronate suggests that cyclic dosing is actually less effective thancontinuous daily dosing for maximizing antiresorptive bone effects. SeeL. Mortensen, et al., Prevention Of Early Postmenopausal Bone Loss ByRisedronate, Journal of Bone and Mineral Research, vol. 10, supp. 1, p.s140 (1995), which is incorporated by reference herein in its entirety.Furthermore, these cyclic regimens do not eliminate or minimize adversegastrointestinal effects, because such regimens typically utilizeperiods of multiple daily dosing. Also, the cyclic regimens arecumbersome to administer and have the disadvantage of low patientcompliance, and consequently compromised therapeutic efficacy. U.S. Pat.No. 5,366,965, to Strein, issued Nov. 22, 1994, which is incorpoated byreference herein in its entirety, attempts to address the problem ofadverse gastrointestinal effects by administering a polyphosphonatecompound, either orally, subcutaneously, or intravenously, according toan intermittent dosing schedule having both a bone resorption inhibitionperiod and a no-treatment rest period. However, the regimen has thedisadvantage of not being continuous and regular, and requiresnontreatment periods ranging from 20 to 120 days. PCT Application No. WO95/30421, to Goodship et al, published Nov. 16, 1995, which isincorporated by reference herein in its entirety, discloses methods forpreventing prosthetic loosening and migration using variousbisphosphonate compounds. Administration of a once weekly partial doseof the bisphosphonate is disclosed. However, the reference specificallyfails to address the issue of adverse gastrointestinal effects or todisclose administration of larger or multiple dosages.

[0011] It is seen from current teachings that both daily and cyclictreatment regimens have shortcomings, and that there is a need fordevelopment of a dosing regimen to overcome these shortcomings.

[0012] In the present invention, it is found that the adversegastrointestinal effects that can be associated with daily or cyclicdosing regimens can be minimized by administering the bisphosphonate ata relatively high unit dosage according to a continuous schedule havinga dosing interval selected from the group consisting of once-weeklydosing, twice-weekly dosing, biweekly dosing, and twice-monthly dosing.In other words, it is found that the administration of a bisphosphonateat a high relative dosage at a low relative dosing frequency causes lessadverse gastrointestinal effects, particularly esophageal effects,compared to the administration of a low relative dosage at a highrelative dosing frequency. This result is surprising in view of theteachings suggesting that adverse gastrointestinal effects would beexpected to increase as a function of increasing bisphosphonate dosage.Such administration methods of the present invention would be especiallybeneficial in treating patients that have been identified as sufferingfrom or are susceptible to upper gastrointestinal disorders, e.g.gastrointestinal reflux disease (i.e. “GERD”), esophagitis, dyspepsia(i.e. heatburn), ulcers, and other related disorders. In such patientsconventional bisphosphonate therapy could potentially exacerbate orinduce such upper gastrointestinal disorders.

[0013] From a patient lifestyle standpoint, the methods of the presentinvention would also be more convenient than daily or cyclic dosingregimens. Patients would be subjected less frequently to theinconvenience of having to take the drug on an empty stomach and havingto fast for at least 30 minutes after dosing. Also, patients would notneed to keep track of a complex dosing regimen. The methods of thepresent invention are likely to have the advantage of promoting betterpatient compliance, which in turn can translate into better therapeuticefficacy.

[0014] It is an object of the present invention to provide methods forinhibiting bone resorption and the conditions associated therewith.

[0015] It is another object of the present invention to provide methodsfor treating abnormal bone resorption and the conditions associatedtherewith.

[0016] It is another object of the present invention to provide methodsfor preventing abnormal bone resorption and the conditions associatedtherewith.

[0017] It is another object of the present invention to provide methodswhich are oral methods.

[0018] It is another object of the present invention to provide suchmethods in humans.

[0019] It is another object of the present invention to provide suchmethods in patients that have been identified as suffering from or aresusceptible to upper gastrointestinal disorders, e.g. gastrointestinalreflux disease (i.e. “GERD”), esophagitis, dyspepsia (i.e. heatburn),ulcers, and other related disorders.

[0020] It is another object of the present invention to provide suchmethods while minimizing the occurrence of or potential for adversegastronintestinal effects.

[0021] It is another object of the present invention to provide suchmethods comprising a continuous dosing schedule having a dosing intervalselected from the group consisting of weekly dosing, twice-weeklydosing, biweekly dosing, and twice-monthly dosing.

[0022] It is another object of the present invention to provide suchmethods comprising a continuous dosing schedule having a dosingperiodicity ranging from about once every 3 days to about once every 16days.

[0023] It is another object of the present invention to provide suchmethods wherein the continuous dosing schedule is maintained until thedesired therapeutic effect is achieved.

[0024] It is another object of the present invention to treat or preventabnormal bone resorption in an osteoporotic mammal, preferably anosteoporotic human.

[0025] It is another object of the present invention to providepharmaceutical compositions and kits useful in the methods herein.

[0026] These and other objects will become readily apparent from thedetailed description which follows.

SUMMARY OF THE INVENTION

[0027] The present invention relates to methods for inhibiting boneresorption in a mammal in need thereof, while minimizing the occurrenceof or potential for adverse gastrointestinal effects, said methodcomprising orally administering to said mammal a pharmaceuticallyeffective amount of a bisphosphonate as a unit dosage according to acontinuous schedule having a dosing interval selected from the groupconsisting of once-weekly dosing, twice-weekly dosing, biweekly dosing,and twice-monthly dosing, wherein said continuous schedule is maintaineduntil the desired therapeutic effect is achieved for said mammal.

[0028] In other embodiments, the present invention relates to methodscomprising a continuous dosing schedule having a dosing periodicityranging from about once every 3 days to about once every 16 days.

[0029] In other embodiments, the present invention relates to methodsfor treating abnormal bone resorption in a mammal in need of suchtreatment.

[0030] In other embodiments, the present invention relates to methodsfor preventing abnormal bone resorption in a mammal in need of suchprevention.

[0031] In other embodiments, the present invention relates to suchmethods useful in humans.

[0032] In other embodiments, the present invention relates to suchmethods useful in humans indentified as having or being susceptible toupper gastrointestinal disorders.

[0033] In other embodiments, the present invention relates to methodsfor treating or preventing osteoporosis in a mammal.

[0034] In other embodiments, the present invention relates to methodsfor treating or preventing osteoporosis in a human.

[0035] In other embodiments, the present invention relates to methodsfor inhibiting bone resorption, or treating or preventing abnormal boneresorption in a human comprising administering to said human from about8.75 mg to about 140 mg, on an alendronic acid active basis, of abisphosphonate selected from the group consisting of alendronate,pharmaceutically acceptable salts thereof, and mixtures thereof.

[0036] In other embodiments the present invention relates to apharmaceutical composition comprising from about 8.75 mg to about 140mg, on an alendronic acid active basis, of a bisphosphonate selectedfrom the group consisting of alendronate, pharmaceutically acceptablesalts thereof, and mixtures thereof.

[0037] All percentages and ratios used herein, unless otherwiseindicated, are by weight. The invention hereof can comprise, consist of,or consist essentially of the essential as well as optional ingredients,components, and methods described herein.

BRIEF DESCRIPTION OF THE FIGURES

[0038]FIG. 1 is a photomicrograph (total magnification 270×) of canineesophagus tissue (paraffin embedded and stained with hematoxylin andeosin) from an animal sacrificed immediately after infusion of the lastof five separate dosages of 50 mL of simulated gastric juiceadministered on five consecutive days.

[0039]FIG. 2 is a photomicrograph (total magnification 270×) of canineesophagus tissue (paraffin embedded and stained with hematoxylin andeosin) from an animal sacrificed immediately after infusion of the lastof five separate dosages of 50 mL of 0.20 mg/mL alendronate in simulatedgastric juice administered on five consecutive days.

[0040]FIG. 3 is a photomicrograph (total magnification 270×) of canineesophagus tissue (paraffin embedded and stained with hematoxylin andeosin) from an animal sacrificed 24 hours after infusion with a singledosage of 50 mL of 0.80 mg/mL alendronate in simulated gastric juice.

[0041]FIG. 4 is a photomicrograph (total magnification 270×) of canineesophagus tissue (paraffin embedded and stained with hematoxylin andeosin) from an animal sacrificed 7 days after infusion with a singledosage of 50 mL of 0.80 mg/mL alendronate in simulated gastric juice.

[0042]FIG. 5 is a photomicrograph (total magnification 270×) of canineesophagus tissue (paraffin embedded and stained with hematoxylin andeosin) from an animal sacrified 7 days after infusion of the last of 4separate dosages of 50 mL of 0.80 mg/mL alendronate in simulated gastricjuice administered once per week, i.e. once every 7 days.

[0043]FIG. 6 is a photomicrograph (total magnification 270×) of canineesophagus tissue (paraffin embedded and stained with hematoxylin andeosin) from an animal sacrified 4 days after infusion of the last of 8separate dosages of 50 mL of 0.40 mg/mL alendronate in simulated gastricjuice administered twice per week, i.e. once every 3-4 days.

[0044]FIG. 7 is a photomicrograph (total magnification 270×) of canineesophagus tissue (paraffin embedded and stained with hematoxylin andeosin) from an animal sacrificed immediately after infusion of the lastof five separate dosages of 50 mL of 0.20 mg/mL risedronate in simulatedgastric juice administered on five consecutive days.

[0045]FIG. 8 is a photomicrograph (total magnification 270×) of canineesophagus tissue (paraffin embedded and stained with hematoxylin andeosin) from an animal sacrificed immediately after infusion of the lastof five separate dosages of 50 mL of 4.0 mg/mL tiludronate in simulatedgastric juice administered on five consecutive days.

DESCRIPTION OF THE INVENTION

[0046] The present invention relates to a method, preferably an oralmethod, for inhibiting bone resorption in a mammal in need thereof,while minimizing the occurrence of or potential for adversegastrointestinal effects. The present invention relates to methods oftreating or preventing abnormal bone resorption in a mammal in need ofsuch treatment or prevention. The methods of the present inventioncomprise orally administering to a mammal a pharmaceutically effectiveamount of a bisphosphonate as a unit dosage, wherein said dosage isadministered according to a continuous schedule having a dosing intervalselected from the group consisting of once-weekly dosing, twice-weeklydosing, biweekly dosing, and twice-monthly dosing. In other embodiments,the present invention relates to methods comprising a continuous dosingschedule having a dosing periodicity ranging from about once every 3days to about once every 16 days. Typically, the continuous dosingschedule is maintained until the desired therapeutic effect is achievedfor the mammal.

[0047] The present invention utilizes higher unit dosages of thebisphosphonate at each dosing point than has heretofore been typicallyadministered, yet because of the dosing schedule chosen, the potentialfor adverse gastrointestinal effects are minimized. Moreover, the methodis more convenient because the disadvantages associated with dailydosing are minimized.

[0048] The methods of the present invention are generally administeredto mammals in need of bisphosphonate therapy. Preferably the mammals arehuman patients, particularly human patients in need of inhibiting boneresorption, such as patients in need of treating or preventing abnormalbone resorption.

[0049] The administration methods of the present invention areespecially useful in administering bisphosphonate therapy to humanpatients that have been identified as suffering from or are susceptibleto upper gastrointestinal disorders, e.g. GERD, esophagitis, dyspepsia,ulcers, etc. In such patients conventional bisphosphonate therapy couldpotentially exacerbate or induce such upper gastrointestinal disorders.

[0050] The term “pharmaceutically effective amount”, as used herein,means that amount of the bisphosphonate compound, that will elicit thedesired therapeutic effect or response when administered in accordancewith the desired treatment regimen. A preferred pharmaceuticallyeffective amount of the bisphosphonate is a bone resorption inhibitingamount.

[0051] The term “minimize the occurrence of or potential for adversegastrointestinal effects”, as used herein, means reducing, preventing,decreasing, or lessening the occurrence of or the potential forincurring unwanted side effects in the gastrointestinal tract, i.e. theesophagus, stomach, intestines, and rectum, particularly the uppergastrointestinal tract, i.e. the esophagus and stomach. Nonlimitingadverse gastrointestinal effects include, but are not limited to GERD,esophagitis, dyspepsia, ulcers, esophageal irritation, esophagealperforation, abdominal pain, and constipation.

[0052] The term “abnormal bone resorption”, as used herein means adegree of bone resorption that exceeds the degree of bone formation,either locally, or in the skeleton as a whole. Alternatively, “abnormalbone resorption” can be associated with the formation of bone having anabnormal structure.

[0053] The term “bone resorption inhibiting”, as used herein, meanstreating or preventing bone resorption by the direct or indirectalteration of osteoclast formation or activity. Inhibition of boneresorption refers to treatment or prevention of bone loss, especiallythe inhibition of removal of existing bone either from the mineral phaseand/or the organic matrix phase, through direct or indirect alterationof osteoclast formation or activity.

[0054] The terms “continuous schedule” or “continuous dosing schedule”,as used herein, mean that the dosing regimen is repeated until thedesired therapeutic effect is achieved. The continuous schedule orcontinuous dosing schedule is distinguished from cyclical orintermittent administration.

[0055] The term “until the desired therapeutic effect is achieved”, asused herein, means that the bisphosphonate compound is continuouslyadministered, according to the dosing schedule chosen, up to the timethat the clinical or medical effect sought for the disease or conditionis observed by the clinician or researcher. For methods of treatment ofthe present invention, the bisphosphonate compound is continuouslyadministered until the desired change in bone mass or structure isobserved. In such instances, achieving an increase in bone mass or areplacement of abnormal bone structure with more normal bone structureare the desired objectives. For methods of prevention of the presentinvention, the bisphosphonate compound is continuously administered foras long as necessary to prevent the undesired condition. In suchinstances, maintenance of bone mass density is often the objective.Nonlimiting examples of administration periods can range from about 2weeks to the remaining lifespan of the mammal. For humans,administration periods can range from about 2 weeks to the remaininglifespan of the human, preferably from about 2 weeks to about 20 years,more preferably from about 1 month to about 20 years, more preferablyfrom about 6 months to about 10 years, and most preferably from about 1year to about 10 years.

[0056] Methods of the Present Invention

[0057] The present invention comprises methods for inhibiting boneresorption in mammals. The present invention also comprises treatingabnormal bone resorption in mammals. The present invention alsocomprises methods for preventing abnormal bone resorption in mammals. Inpreferred embodiments of the present invention, the mammal is a human.

[0058] The methods of the present invention do not have thedisadvantages of current methods of treatment which can cause orincrease the potential for adverse gastrointestinal effects or whichrequire cumbersome, irregular, or complicated dosing regimens.

[0059] The present invention comprises a continuous dosing schedulewhereby a unit dosage of the bisphosphonate is regularly administeredaccording to a dosing interval selected from the group consisting ofonce-weekly dosing, twice-weekly dosing, biweekly dosing, andtwice-monthly dosing.

[0060] By once-weekly dosing is meant that a unit dosage of thebisphosphonate is administered once a week, i.e. one time during a sevenday period, preferably on the same day of each week. In the once-weeklydosing regimen, the unit dosage is generally administered about everyseven days. A nonlimiting example of a once-weekly dosing regimen wouldentail the administration of a unit dosage of the bisphosphonate everySunday. It is preferred that the unit dosage is not administered onconsecutive days, but the once-weekly dosing regimen can include adosing regimen in which unit dosages are administered on two consecutivedays falling within two different weekly periods.

[0061] By twice-weekly dosing is meant that a unit dosage of thebisphosphonate is administered twice a week, i.e. two times during aseven day period, preferably on the same two days of each weekly period.In the twice-weekly dosing regimen, each unit dosage is generallyadministered about every three to four days. A nonlimiting example of atwice-weekly dosing regimen would entail the administration of a unitdosage of the bisphosphonate every Sunday and Wednesday. It is preferredthat the unit dosages are not administered on the same or consecutivedays, but the twice-weekly dosing regimen can include a dosing regimenin which unit dosages are administered on two consecutive days within aweekly period or different weekly periods.

[0062] By biweekly dosing is meant that a unit dosage of thebisphosphonate is administered once during a two week period, i.e. onetime during a fourteen day period, preferably on the same day duringeach two week period. In the twice-weekly dosing regimen, each unitdosage is generally administered about every fourteen days. Anonlimiting example of a biweekly dosing regimen would entail theadministration of a unit dosage of the bisphosphonate every otherSunday. It is preferred that the unit dosage is not administered onconsecutive days, but the biweekly dosing regimen can include a dosingregimen in which the unit dosage is administered on two consecutive dayswithin two different biweekly periods.

[0063] By twice-monthly dosing is meant that a unit dosage of thebisphosphonate is administered twice, i.e. two times, during a monthlycalendar period. With the twice-monthly regimen, the doses arepreferably given on the same two dates of each month. In thetwice-monthly dosing regimen, each unit dosage is generally administeredabout every fourteen to sixteen days. A nonlimiting example of abiweekly dosing regimen would entail dosing on or about the first of themonth and on or about the fifteenth, i.e. the midway point, of themonth. It is preferred that the unit dosages are not administered on thesame or consecutive days but the twice-monthly dosing regimen caninclude a dosing regimen in which the unit dosages are administered ontwo consecutive days within a monthly period, or different monthlyperiods. The twice-monthly regimen is defined herein as being distinctfrom, and not encompassing, the biweekly dosing regimen because the tworegimens have a different periodicity and result in the administrationof different numbers of dosages over long periods of time. For example,over a one year period, a total of about twenty four dosages would beadministered according to the twice-monthly regimen (because there aretwelve calendar months in a year), whereas a total of about twenty sixdosages would be administered according to the biweekly dosing regimen(because there are about fifty-two weeks in a year).

[0064] In further embodiments or descriptions of the present invention,the unit dosage is given with a periodicity ranging from about onceevery 3 days to about once every 16 days.

[0065] The methods and compositions of the present invention are usefulfor inhibiting bone resorption and for treating and preventing abnormalbone resorption and conditions associated therewith. Such conditionsinclude both generalized and localized bone loss. Also, the creation ofbone having an abnormal structure, as in Paget's disease, can beassociated with abnormal bone resorption. The term “generalized boneloss” means bone loss at multiple skeletal sites or throughout theskeletal system. The term “localized bone loss” means bone loss at oneor more specific, defined skeletal sites.

[0066] Generalized boss loss is often associated with osteoporosis.Osteoporosis is most common in post-menopausal women, wherein estrogenproduction has been greatly diminished. However, osteoporosis can alsobe steroid-induced and has been observed in males due to age.Osteoporosis can be induced by disease, e.g. rheumatoid arthritis, itcan be induced by secondary causes, e.g., glucocorticoid therapy, or itcan come about with no identifiable cause, i.e. idiopathic osteoporosis.In the present invention, preferred methods include the treatment orprevention of abnormal bone resorption in osteoporotic humans.

[0067] Localized bone loss has been associated with periodontal disease,with bone fractures, and with periprosthetic osteolysis (in other wordswhere bone resorption has occured in proximity to a prosthetic implant).

[0068] Generalized or localized bone loss can occur from disuse, whichis often a problem for those confined to a bed or a wheelchair, or forthose who have an immobilized limb set in a cast or in traction.

[0069] The methods and compositions of the present invention are usefulfor treating and or preventing the following conditions or diseasestates: osteoporosis, which can include post-menopausal osteoporosis,steroid-induced osteoporosis, male osteoporosis, disease-inducedosteoporosis, idiopathic osteoporosis; Paget's disease; abnormallyincreased bone turnover; periodontal disease; localized bone lossassociated with periprosthetic osteolysis; and bone fractures.

[0070] The methods of the present invention are intended to specificallyexclude methods for the treatment and/or prevention of prosthesisloosening and prosthesis migration in mammals as described in PCTapplication WO 95/30421, to Goodship et al, published Nov. 16, 1995,which is incorporated by reference herein in its entirety.

[0071] Bisphosphonates

[0072] The methods and compositions of the present invention comprise abisphosphonate. The bisphosphonates of the present invention correspondto the chemical formula

[0073] wherein

[0074] A and X are independently selected from the group consisting ofH, OH, halogen, NH₂, SH, phenyl, C1-C30 alkyl, C1-C30 substituted alkyl,C1-C10 alkyl or dialkyl substituted NH2, C1-C10 alkoxy, C1-C10 alkyl orphenyl substituted thio, C1-C10 alkyl substituted phenyl, pyridyl,furanyl, pyrrolidinyl, imidazonyl, and benzyl.

[0075] In the foregoing chemical formula, the alkyl groups can bestraight, branched, or cyclic, provided sufficient atoms are selectedfor the chemical formula. The C1-C30 substituted alkyl can include awide variety of substituents, nonlimiting examples which include thoseselected from the group consisting of phenyl, pyridyl, furanyl,pyrrolidinyl, imidazonyl, NH₂, C1-C10 alkyl or dialkyl substituted NH₂,OH, SH, and C1-C10 alkoxy.

[0076] In the foregoing chemical formula, A can include X and X caninclude A such that the two moieties can form part of the same cyclicstructure.

[0077] The foregoing chemical formula is also intended to encompasscomplex carbocyclic, aromatic and hetero atom structures for the Aand/or X substituents, nonlimiting examples of which include naphthyl,quinolyl, isoquinolyl, adamantyl, and chlorophenylthio.

[0078] Preferred structures are those in which A is selected from thegroup consisting of H, OH, and halogen, and X is selected from the groupconsisting of C1-C30 alkyl, C1-C30 substituted alkyl, halogen, andC1-C10 alkyl or phenyl substituted thio.

[0079] More preferred structures are those in which A is selected fromthe group consisting of H, OH, and Cl, and X is selected from the groupconsisting of C1-C30 alkyl, C1-C30 substituted alkyl, Cl, andchlorophenylthio.

[0080] Most preferred is when A is OH and X is a 3-aminopropyl moiety,so that the resulting compound is a4-amino-1,-hydroxybutylidene-1,1-bisphosphonate, i.e. alendronate.

[0081] Pharmaceutically acceptable salts and derivatives of thebisphosphonates are also useful herein. Nonlimiting examples of saltsinclude those selected from the group consisting alkali metal, alkalinemetal, ammonium, and mono-, di, tri-, or tetra-C1-C30-alkyl-substitutedammonium. Preferred salts are those selected from the group consistingof sodium, potassium, calcium, magnesium, and ammonium salts.Nonlimiting examples of derivatives include those selected from thegroup consisting of esters, hydrates, and amides.

[0082] “Pharmaceutically acceptable” as used herein means that the saltsand derivatives of the bisphosphonates have the same generalpharmacological properties as the free acid form from which they arederived and are acceptable from a toxicity viewpoint.

[0083] It should be noted that the terms “bisphosphonate” and“bisphosphonates”, as used herein in referring to the therapeutic agentsof the present invention are meant to also encompass diphosphonates,biphosphonic acids, and diphosphonic acids, as well as salts andderivatives of these materials. The use of a specific nomenclature inreferring to the bisphosphonate or bisphosphonates is not meant to limitthe scope of the present invention, unless specifically indicated.Because of the mixed nomenclature currently in use by those or ordinaryskill in the art, reference to a specific weight or percentage of abisphosphonate compound in the present invention is on an acid activeweight basis, unless indicated otherwise herein. For example, the phrase“about 70 mg of a bone resorption inhibiting bisphosphonate selectedfrom the group consisting of alendronate, pharmaceutically acceptablesalts thereof, and mixtures thereof, on an alendronic acid active weightbasis” means that the amount of the bisphosphonate compound selected iscalculated based on 70 mg of alendronic acid.

[0084] Nonlimiting examples of bisphosphonates useful herein include thefollowing:

[0085] Alendronic acid, 4-amino-1-hydroxybutylidene-1,1-bisphosphonicacid.

[0086] Alendronate (also known as alendronate sodium or monosodiumtrihydrate), 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acidmonosodium trihydrate.

[0087] Alendronic acid and alendronate are described in U.S. Pat. No.4,922,007, to Kieczykowski et al., issued May 1, 1990, and U.S. Pat. No.5,019,651, to Kieczykowski, issued May 28, 1991, both of which areincorporated by reference herein in their entirety.

[0088] Cycloheptylaminomethylene-1,1-bisphosphonic acid, YM 175,Yamanouchi (cimadronate), as described in U.S. Pat. No. 4,970,335, toIsomura et al., issued Nov. 13, 1990, which is incorporated by referenceherein in its entirety.

[0089] 1,1-dichloromethylene-1,1-diphosphonic acid (clodronic acid), andthe disodium salt (clodronate, Procter and Gamble), are described inBelgium Patent 672,205 (1966) and J. Org. Chem 32, 4111 (1967), both ofwhich are incorporated by reference herein in their entirety.

[0090] 1-hydroxy-3-(1-pyrrolidinyl)-propylidene-1,1-bisphosphonic acid(EB-1053).

[0091] 1-hydroxyethane-1,1-diphosphonic acid (etidronic acid).

[0092] 1-hydroxy-3-(N-methyl-N-pentylamino)propylidene-1,1-bisphosphonicacid, also known as BM-210955, Boehringer-Mannheim (ibandronate), isdescribed in U.S. Pat. No. 4,927,814, issued May 22, 1990, which isincorporated by reference herein in its entirety.

[0093] 6-amino-1-hydroxyhexylidene-1,1-bisphosphonic acid (neridronate).

[0094] 3-(dimethylamino)-1-hydroxypropylidene-1,1-bisphosphonic acid(olpadronate).

[0095] 3-amino-1-hydroxypropylidene-1,1-bisphosphonic acid(pamidronate).

[0096] [2-(2-pyridinyl)ethylidene]-1,1-bisphosphonic acid (piridronate)is described in U.S. Pat. No. 4,761,406, which is incorporated byreference in its entirety.

[0097] 1-hydroxy-2-(3-pyridinyl)-ethylidene-1,1-bisphosphonic acid(risedronate).

[0098] (4-chlorophenyl)thiomethane-1,1-disphosphonic acid (tiludronate)as described in U.S. Pat. No. 4,876,248, to Breliere et al., Oct. 24,1989, which is incorporated by reference herein in its entirety.

[0099] 1-hydroxy-2-(lH-imidazol-1-yl)ethylidene-1,1-bisphosphonic acid(zolendronate).

[0100] Preferred are bisphosphonates selected from the group consistingof alendronate, cimadronate, clodronate, tiludronate, etidronate,ibandronate, risedronate, piridronate, pamidronate, zolendronate,pharmaceutically acceptable salts thereof, and mixtures thereof.

[0101] More preferred is alendronate, pharmaceutically acceptable saltsthereof, and mixtures thereof.

[0102] Most preferred is alendronate monosodium trihydrate.

[0103] Pharmaceutical Compositions

[0104] Compositions useful in the present invention comprise apharmaceutically effective amount of a bisphosphonate. Thebisphosphonate is typically administered in admixture with suitablepharmaceutical diluents, excipients, or carriers, collectively referredto herein as “carrier materials”, suitably selected with respect to oraladministration, i.e. tablets, capsules, elixirs, syrups, effervescentcompositions, powders, and the like, and consistent with conventionalpharmaceutical practices. For example, for oral administration in theform of a tablet, capsule, or powder, the active ingredient can becombined with an oral, non-toxic, pharmaceutically acceptable inertcarrier such as lactose, starch, sucrose, glucose, methyl cellulose,magnesium stearate, mannitol, sorbitol, croscarmellose sodium and thelike; for oral administration in liquid form, e.g., elixirs and syrups,effervescent compositions, the oral drug components can be combined withany oral, non-toxic, pharmaceutically acceptable inert carrier such asethanol, glycerol, water and the like. Moreover, when desired ornecessary, suitable binders, lubricants, disintegrating agents, buffers,coatings, and coloring agents can also be incorporated. Suitable binderscan include starch, gelatin, natural sugars such a glucose, anhydrouslactose, free-flow lactose, beta-lactose, and corn sweeteners, naturaland synthetic gums, such as acacia, guar, tragacanth or sodium alginate,carboxymethyl cellulose, polyethylene glycol, waxes, and the like.Lubricants used in these dosage forms include sodium oleate, sodiumstearate, magnesium stearate, sodium benzoate, sodium acetate, sodiumchloride and the like. A particularly preferred tablet formulation foralendronate monosodium trihydrate is that described in U.S. Pat. No.5,358,941, to Bechard et al, issued Oct. 25, 1994, which is incorporatedby reference herein in its entirety. The compounds used in the presentmethod can also be coupled with soluble polymers as targetable drugcarriers. Such polymers can include polyvinylpyrrolidone, pyrancopolymer, polyhydroxylpropyl-methacrylamide, and the like.

[0105] The precise dosage of the bisphonate will vary with the dosingschedule, the oral potency of the particular bisphosphonate chosen, theage, size, sex and condition of the mammal or human, the nature andseverity of the disorder to be treated, and other relevant medical andphysical factors. Thus, a precise pharmaceutically effective amountcannot be specified in advance and can be readily determined by thecaregiver or clinician. Appropriate amounts can be determined by routineexperimentation from animal models and human clinical studies.Generally, an appropriate amount of bisphosphonate is chosen to obtain abone resorption inhibiting effect, i.e. a bone resorption inhibitingamount of the bisphosphonate is administered. For humans, an effectiveoral dose of bisphosphonate is typically from about 1.5 to about 6000μg/kg body weight and preferably about 10 to about 2000 μg/kg of bodyweight.

[0106] For human oral compositions comprising alendronate,pharmaceutically acceptable salts thereof, or pharmaceuticallyacceptable derivatives thereof, a unit dosage typically comprises fromabout 8.75 mg to about 140 mg of the alendronate compound, on analendronic acid active weight basis.

[0107] For once-weekly dosing, an oral unit dosage comprises from about17.5 mg to about 70 mg of the alendronate compound, on an alendronicacid active weight basis. Examples of weekly oral dosages include a unitdosage which is useful for osteoporosis prevention comprising about 35mg of the alendronate compound, and a unit dosage which is useful fortreating osteoporosis comprising about 70 mg of the alendronatecompound.

[0108] For twice-weekly dosing, an oral unit dosage comprises from about8.75 mg to about 35 mg of the alendronate compound, on an alendronicacid active weight basis. Examples of twice-weekly oral dosages includea unit dosage which is useful for osteoporosis prevention comprisingabout 17.5 mg of the alendronate compound, and a unit dosage which isuseful for osteoporosis treatment, comprising about 35 mg of thealendronate compound.

[0109] For biweekly or twice-monthly dosing, an oral unit dosagecomprises from about 35 mg to about 140 mg of the alendronate compound,on an alendronic acid active weight basis. Examples of biweekly ortwice-monthly oral dosages include a unit dosage which is useful forosteoporosis prevention comprising about 70 mg of the alendronatecompound, and a unit dosage which is useful for osteoporosis treatment,comprising about 140 mg of the alendronate compound.

[0110] Nonlimiting examples of oral compositions comprising alendronate,as well as other bisphosphonates, are illustrated in the Examples,below.

[0111] Sequential Administration of Histamine H2 Receptor Blockersand/or Proton Pump Inhibitors With Bisphosphonates

[0112] In further embodiments, the methods and compositions of thepresent invention can also comprise a histamine H2 receptor blocker(i.e. antagonist) and/or a proton pump inhibitor. Histamine H2 receptorblockers and proton pump inhibitors are well known therapeutic agentsfor increasing gastric pH. See L. J. Hixson, et al., Current Trends inthe Pharmacotherapy for Peptic Ulcer Disease, Arch. Intern. Med., vol.152, pp. 726-732 (April 1992), which is incorporated by reference hereinin its entirety. It is found in the present invention that thesequential oral administration of a histamine H2 receptor blocker and/ora proton pump inhibitor, followed by a bisphosphonate can help tofurther minimize adverse gastrointestinal effects. In these embodiments,the histamine H2 receptor blocker and/or proton pump inhibitor isadministered from about 30 minutes to about 24 hours prior to theadministration of the bisphosphonate. In more preferred embodiments, thehistamine H2 receptor blocker and/or proton pump inhibitor isadministered from about 30 minutes to about 12 hours prior to theadministration of the bisphonate.

[0113] The dosage of the histamine H2 receptor blocker and/or protonpump inhibitor will depend upon the particular compound selected andfactors associated with the mammal to be treated, i.e. size, health,etc.

[0114] Nonlimiting examples of histamine H2 receptor blockers and/orproton pump inhibitors include those selected from the group consistingof cimetidine, famotidine, nizatidine, ranitidine, omprazole, andlansoprazole.

[0115] Treatment Kits

[0116] In further embodiments, the present invention relates to a kitfor conveniently and effectively carrying out the methods in accordancewith the present invention. Such kits are especially suited for thedelivery of solid oral forms such as tablets or capsules. Such a kitpreferably includes a number of unit dosages. Such kits can include acard having the dosages oriented in the order of their intended use. Anexample of such a kit is a “blister pack”. Blister packs are well knownin the packaging industry and are widely used for packagingpharmaceutical unit dosage forms. If desired, a memory aid can beprovided, for example in the form of numbers, letters, or other markingsor with a calendar insert, designating the days in the treatmentschedule in which the dosages can be administered. Alternatively,placebo dosages, or calcium or dietary supplements, either in a formsimilar to or distinct from the bisphosphonate dosages, can be includedto provide a kit in which a dosage is taken every day. In thoseembodiments including a histamine H2 receptor and/or proton pumpinhibitor, these agents can be included as part of the kit.

EXAMPLES

[0117] The following examples further describe and demonstrateembodiments within the scope of the present invention. The examples aregiven solely for the purpose of illustration and are not to be construedas limitations of the present invention as many variations thereof arepossible without departing from the spirit and scope of the invention.

Example 1

[0118] Esophageal Irritation Potential

[0119] The esophageal irritation potential of the bisphosphonates isevaluated using a dog model.

[0120] The experiments demonstrate the relative irritation potential ofthe following dosing regimens: placebo (Group 1), a single highconcentration dosage of alendronate monosodium trihydrate (Group 2), alow concentration dosage of alendronate monosodium trihydrateadministered for five consecutive days (Groups 3 and 4), a highconcentration dosage of alendronate monosodium trihydrate administeredonce per week for four weeks (Group 5), a mid-range concentration dosageof alendronate monosodium trihydrate administered twice per week forfour weeks (Group 6), a low dosage of risedronate sodium administeredfor five consecutive days (Group 7), and a low dosage of tiludronatedisodium administered for five consecutive days (Group 8).

[0121] The following solutions are prepared:

[0122] (1) simulated gastric juice (pH about 2), i.e. the controlsolution.

[0123] (2) simulated gastric juice (pH about 2) containing about 0.20mg/mL of alendronate monosodium trihydrate on an alendronic acid activebasis.

[0124] (3) simulated gastric juice (pH about 2) containing about 0.80mg/mL of alendronate monosodium trihydrate on an alendronic acid activebasis.

[0125] (4) simulated gastric juice (pH about 2) containing about 0.40mg/mL of alendronate monosodium trihydrate on an alendronic acid activebasis.

[0126] (5) simulated gastric juice (pH about 2) containing about 0.20mg/mL of risedronate sodium on a risedronic acid active basis.

[0127] (6) simulated gastric juice (pH about 2) containing about 4.0mg/mL of tiludronate disodium on a tiludronic acid active basis.

[0128] The simulated gastric juice is prepared by dissolving about 960mg of pepsin (L-585,228000B003, Fisher Chemical) in about 147 mL of 0.90(wt %) NaCl (aqueous), adding about 3 mL of 1.0 M HCl (aqueous), andadjusting the volume to about 300 mL with deionized water. The pH of theresulting solution is measured and if necessary is adjusted to about 2using 1.0 M HCl (aqueous) or 1.0 M NaOH (aqueous).

[0129] The animals used in the experiments are anesthetized andadministered about 50 mL of the appropriate solution over about 30minutes by infusion into the esophagus using an infusion pump and arubber catheter. The following treatment experiments are run:

[0130] Group 1: This control group contains four animals. Each animal isadministered a dosage of about 50 mL of simulated gastric juice[solution (1)] on each of five consecutive days. The animals aresacrificed immediately after the last dose is administered.

[0131] Group 2: This group contains four animals. Each animal isadministered a dosage of about 50 mL of simulated gastric juicecontaining about 0.20 mg/mL of alendronate [solution (2)] on each offive consecutive days. The animals are sacrificed immediately after thelast dose is administered.

[0132] Group 3: This group contains five animals. Each animal isadministered a dosage of about 50 mL of simulated gastric juicecontaining about 0.80 mg/mL of alendronate [solution (3)] on a singletreatment day. The animals are sacrificed about 24 hours after the doseis administered.

[0133] Group 4: This group contains five animals. Each animal isadministered a dosage of about 50 mL of simulated gastric juicecontaining about 0.80 mg/mL of alendronate [solution (3)] on a singletreatment day. The animals are sacrificed about 7 days after the dose isadministered.

[0134] Group 5: This group contains six animals. Each animal isadministered a dosage of about 50 mL of simulated gastric juicecontaining about 0.80 mg/mL of alendronate [solution (3)] once per week,i.e. every seven days, for four weeks. The animals are administered atotal of four dosages. The animals are sacrificed about 7 days after thelast dose is administered.

[0135] Group 6: This group contains six animals. Each animal isadministered a dosage of about 50 mL of simulated gastric juicecontaining about 0.40 mg/mL of alendronate [solution (4)] twice perweek, i.e. every three to four days, for four weeks. The animals areadministered a total of eight dosages. The animals are sacrificed aboutfour days after the last dose is administered.

[0136] Group 7: This group contains eight animals. Each animal isadministered a dosage of about 50 mL of simulated gastric juicecontaining about 0.20 mg/mL of risedronate [solution (5)] on each offive consecutive days. The animals are sacrificed immediately after thelast dose is administered.

[0137] Group 8: This group contains four animals. Each animal isadministered a dosage of about 50 mL of simulated gastric juicecontaining about 4.0 mg/mL of tiludronate [solution (6)] on each of fiveconsecutive days. The animals are sacrificed immediately after the lastdose is administered.

[0138] The esophagus from each sacrificed animal is removed and preparedfor histopathology using standard techniques by embedding the tissue inparaffin, staining with hematoxylin and eosin. The sections are examinedmicroscopically. The histopathology results are summarized in Table 1.

[0139] For the Group 1 animals (control group), the photomicrographsshow that the esophagus is normal with an intact epithelium and absenceof inflammatory cells in the submucosa. FIG. 1 is a representativephotomicrograph from a Group 1 animal.

[0140] For the Group 2 animals, the photomicrographs show that theesophagus exhibits deep ulceration of the epithelial surface and markedsubmucosal inflammation and vacuolation. FIG. 2 is a representativephotomicrograph from a Group 2 animal.

[0141] For the Group 3 animals, the photomicrographs show that theesophagus has an intact epithelial surface with very slight submucosalinflammation and vacuolation. FIG. 3 is a representative photomicrographfrom a Group 3 animal.

[0142] For the Group 4 animals, the photomicrographs show that theesosphagus has an intact epithelium with either minimal inflammation(two of the five animals) or no inflammation (three of the five animals)and no vacuolation. FIG. 4 is a representative photomicrograph from aGroup 4 animal exhibiting minimal inflammation.

[0143] For the Group 5 animals, the photomicrographs show that theesophagus is normal with an intact epithelium and absence ofinflammatory cells in the submucosa. FIG. 5 is a representativephotomicrograph from a Group 5 animal.

[0144] For the Group 6 animals, the photomicrographs show that theesophagus exhibits deep ulceration of the epithelial surface and markedsubmucosal inflammation and vacuolation. FIG. 6 is a representativephotomicrograph from a Group 6 animal.

[0145] For the Group 7 animals, the photomicrographs show that theesophagus exhibits deep ulceration of the epithelial surface and markedsubmucosal inflammation and vacuolation. FIG. 7 is a representativephotomicrograph from a Group 7 animal.

[0146] For the Group 8 animals, the photomicrographs show that theesophagus exhibits slight ulceration of the epithelial surface andslight submucosal inflammation and vacuolation. FIG. 8 is arepresentative photomicrograph from a Group 8 animal.

[0147] These experiments demonstrate that considerably less esophagealirritation (comparable to control Group 1)is observed from theadministration of a single high concentration dosage of alendronate(Groups 3 and 4) versus administration of low concentration dosages onconsecutive days (Group 2). These experiments also demonstrateconsideraly less esophageal irritation is observed from theadministration of a single high concentration of alendronate on a weeklybasis (Group 5) or twice-weekly basis (Group 6) versus administration oflow concentration dosages on consecutive days (Group 2). Theseexperiments also demonstrate that when other bisphosphonates such asrisedronate (Group 7) or tiludronate (Group 8) are administered at lowdosages on consecutive days that the esophageal irritation potential ishigh. TABLE 1 Esophageal Irritation Potential Studies Active AgentDosing Sacrifice Histo- Group mg/mL Schedule Time pathology 1 0 1X dailyimmediately Normal. Intact (n = 4) for 5 days after epithelium and lastabsence of dosing inflammatory cells in the submucosa. 2 Alendronate 1Xdaily immediately Deep ulceration of (n = 4) 0.20 for 5 days afterepithelial surface. last Marked submucosal dosing inflammation andvacuolation. 3 Alendronate 1X 24 hours Intact epithelial (n = 5) 0.80after surface with very dosing slight submucosal inflammation andvacuolation. 4 Alendronate 1X 7 days Intact epithelium (n = 5) 0.80after with either minimal dosing inflammation (2 of 5 animals) or noinflammation (3 of 5 animals) and no vacuolation. 5 Alendronate 1X 7days Intact epithelium (n = 6) 0.80 weekly after last with no for atotal dosing inflammation and no of 4 doses vacuolation. 6 Alendronate2X immediately Deep ulceration of (n = 6) 0.40 weekly after epithelialsurface. for 4 last Marked submucosal weeks dosing inflammation andvacuolation. 7 Risedronate 1X daily immediately Deep ulceration of (n =8) 0.20 for 5 days ly after epithelial surface (4 last of 8 animals).dosing Marked submucosal inflammation and vacuolation. 8 Tiludronate 1Xdaily 24 hours Slight submucosal (n = 4) 4.0 for 5 days after lastinflammation and dosing vacuolation (3 of 4 animals, including 1 ofthese animals with slight ulceration).

Example 2

[0148] Once-weekly Dosing Regimen.

[0149] Treatment of Osteoporosis.

[0150] Alendronate tablets or liquid formulations containing about 70 mgof alendronate, on an alendronic acid active basis, are prepared (seeEXAMPLES 7 and 8). The tablets or liquid formulations are orallyadministered to a human patient once-weekly, i.e. preferably about onceevery seven days (for example, every Sunday), for a period of at leastone year. This method of administration is useful and convenient fortreating osteoporosis and for minimizing adverse gastrointestinaleffects, particularly adverse esophageal effects. This method is alsouseful for improving patient acceptance and compliance.

[0151] Prevention of Osteoporosis.

[0152] Alendronate tablets or liquid formulations containing about 35 mgof alendronate, on an alendronic acid active basis, are prepared (seeEXAMPLES 7 and 8). The tablets or liquid formulations are orallyadministered to a human patient once-weekly, i.e. preferably about onceevery seven days (for example, every Sunday), for a period of at leastone year. This method of administration is useful and convenient forpreventing osteoporosis and for minimizing adverse gastrointestinaleffects, particularly adverse esophageal effects. This method is alsouseful for improving patient acceptance and compliance.

Example 3

[0153] Twice-weekly Dosing Regimen.

[0154] Treatment of Osteoporosis.

[0155] Alendronate tablets or liquid formulations containing about 35 mgof alendronate, on an alendronic acid active basis, are prepared (seeEXAMPLES 7 and 8). The tablets or liquid formulations are orallyadministered to a human patient twice-weekly, preferably about onceevery three or four days (for example, every Sunday and Wednesday), fora period of at least one year. This method of administration is usefuland convenient for treating osteoporosis and for minimizing adversegastrointestinal effects, particularly adverse esophageal effects. Thismethod is also useful for improving patient acceptance and compliance.

[0156] Prevention of Osteoporosis.

[0157] Alendronate tablets or liquid formulations containing about 17.5mg of alendronate, on an alendronic acid active basis, are prepared (seeEXAMPLES 7 and 8). The tablets or liquid formulations are orallyadministered to a human patient twice-weekly, preferably about onceevery three or four days (for example, every Sunday and Wednesday), fora period of at least one year. This method of administration is usefuland convenient for preventing osteoporosis and for minimizing adversegastrointestinal effects, particularly adverse esophageal effects. Thismethod is also useful for improving patient acceptance and compliance.

Example 4

[0158] Biweekly Dosing Regimen

[0159] Treatment of Osteoporosis.

[0160] Alendronate tablets or liquid formulations containing about 140mg of alendronate, on an alendronic acid active basis, are prepared (seeEXAMPLES 7 and 8). The tablets or liquid formulations are orallyadministered to a human patient biweekly, i.e. preferably about onceevery fourteen days (for example, on alternate Sundays), for a period ofat least one year. This method of administration is useful andconvenient for treating osteoporosis and for minimizing adversegastrointestinal effects, particularly adverse esophageal effects. Thismethod is also useful for improving patient acceptance and compliance.

[0161] Prevention of Osteoporosis.

[0162] Alendronate tablets or liquid formulations containing about 70 mgof alendronate, on an alendronic acid active basis, are prepared (seeEXAMPLES 7 and 8). The tablets or liquid formulations are orallyadministered to a human patient biweekly, i.e. preferably about onceevery fourteen days (for example, on alternate Sundays), for a period ofat least one year. This method of administration is useful andconvenient for preventing osteoporosis and for minimizing adversegastrointestinal effects, particularly adverse esophageal effects. Thismethod is also useful for improving patient acceptance and compliance.

Example 5

[0163] Twice-monthly Dosing Regimen.

[0164] Treatment of Osteoporosis.

[0165] Alendronate tablets or liquid formulations containing about 140mg of alendronate, on an alendronic acid active basis, are prepared (seeEXAMPLES 7 and 8). The tablets or liquid formulations are orallyadministered to a human twice-monthly, i.e. preferably about once everyfourteen to sixteen days (for example, on about the first and fifteenthof each month), for a period of at least one year. This method ofadministration is useful and convenient for treating osteoporosis andfor minimizing adverse gastrointestinal effects, particularly adverseesophageal effects. This method is also useful for improving patientacceptance and compliance.

[0166] Prevention of Osteoporosis.

[0167] Alendronate tablets or liquid formulations containing about 70 mgof alendronate, on an alendronic acid active basis, are prepared (seeEXAMPLES 7 and 8). The tablets or liquid formulations are orallyadministered to a human patient biweekly, i.e. preferably once everyfourteen to sixteen days (for example, on about the first and fifteenthof each month), for a period of at least one year. This method ofadministration is useful and convenient for preventing osteoporosis andfor minimizing adverse gastrointestinal effects, particularly adverseesophageal effects. This method is also useful for improving patientacceptance and compliance.

Example 6

[0168] In further embodiments, alendronate tablets or liquidformulations are orally dosed, at the desired dosage, according to thedosing schedules of EXAMPLES 2-5, for treating or preventing otherdisorders associated with abnormal bone resorption.

[0169] In yet further embodiments, other bisphosphonate compounds areorally dosed, at the desired dosage, according to the dosing schedulesof EXAMPLES 2-5, for treating or preventing osteoporosis or for treatingor preventing other conditions associated with abnormal bone resorption.

Example 7

[0170] Bisphosphonate Tablets.

[0171] Bisphosphonate containing tablets are prepared using standardmixing and formation techniques as described in U.S. Pat. No. 5,358,941,to Bechard et al., issued Oct. 25, 1994, which is incorporated byreference herein in its entirety.

[0172] Tablets containing about 35 mg of alendronate, on an alendronicacid active basis, are prepared using the following relative weights ofingredients. Ingredient Per Tablet Per 4000 Tablets AlendronateMonosodium 45.68 mg 182.72 g Trihydrate Anhydrous Lactose, NF 71.32 mg285.28 g Microcrystalline Cellulose, 80.0 mg 320.0 g NF MagnesiumStearate, NF 1.0 mg 4.0 g Croscarmellose Sodium, NF 2.0 mg 8.0 g

[0173] The resulting tablets are useful for administration in accordancewith the methods of the present invention for inhibiting boneresorption.

[0174] Similarly, tablets comprising other relative weights ofalendronate, on an alendronic acid active basis are prepared: e.g.,about 8.75, 17.5, 70, and 140 mg per tablet. Also, tablets containingother bisphosphonates at appropriate active levels are similarlyprepared: e.g., cimadronate, clodronate, tiludronate, etidronate,ibandronate, risedronate, piridronate, pamidronate, zolendronate, andpharmaceutically acceptable salts thereof. Also, tablets containingcombinations of bisphosphonates are similarly prepared.

Example 8

[0175] Liquid Bisphosphonate Formulation.

[0176] Liquid bisphosphonate formulations are prepared using standardmixing techniques.

[0177] A liquid formulation containing about 70 mg of alendronatemonosodium trihydrate, on an alendronic acid active basis, per about 75mL of liquid is prepared using the following relative weights ofingredients. Ingredient Weight Alendronate Monosodium 91.35 mgTrihydrate Sodium Propylparaben 22.5 mg Sodium Butylparaben 7.5 mgSodium Citrate Dihydrate 1500 mg Citric Acid Anhydrous 56.25 mg SodiumSaccharin 7.5 mg Water qs 75 mL 1 N Sodium Hydroxide (aq) qs pH 6.75

[0178] The resulting liquid formulation is useful for administration asa unit dosage in accordance with the methods of the present inventionfor inhibiting bone resorption.

[0179] Similarly, liquid formulations comprising other relative weightsof alendronate, on an alendronic acid active basis, per unit dosage areprepared: e.g., about 8.75, 17.5, 35, and 140 mg per 75 mL volume. Also,the liquid formulations are prepared to provide other volumes for theunit dosage, e.g. about 135 mL. Also, the liquid formulations areprepared containing other bisphosphonates at appropriate active levels:e.g., cimadronate, clodronate, tiludronate, etidronate, ibandronate,risedronate, piridronate, pamidronate, zolendronate, andpharmaceutically acceptable salts thereof. Also, liquid formulationscontaining combinations of bisphosphonates are similarly prepared.

What is claimed is:
 1. A method for inhibiting bone resorption in amammal, said method comprising orally administering to said mammal apharmaceutically effective amount of a bisphosphonate as a unit dosageaccording to a continuous schedule having a dosing interval selectedfrom the group consisting of once-weekly dosing, twice-weekly dosing,biweekly dosing, and twice-monthly dosing.
 2. A method according toclaim 1 wherein said bisphosphonate is selected from the groupconsisting of alendronate, cimadronate, clodronate, tiludronate,etidronate, ibandronate, risedronate, piridronate, pamidronate,zolendronate, pharmaceutically acceptable salts thereof, and mixturesthereof.
 3. A method according to claim 1 wherein said bisphosphonate isselected from the group consisting of alendronate, pharmaceuticallyacceptable salts thereof, and mixtures thereof.
 4. A method according toclaim 3 wherein said pharmaceutically acceptable salt is alendronatemonosodium trihydrate.
 5. A method according to claim 4 wherein saidmammal is a human.
 6. A method for treating osteoporosis in a mammal inneed of such treatment, said method comprising orally administering tosaid mammal a pharmaceutically effective amount of a bisphosphonate as aunit dosage according to a continuous schedule having a dosing intervalselected from the group consisting of once-weekly dosing, twice-weeklydosing, biweekly dosing, and twice-monthly dosing.
 7. A method accordingto claim 6 wherein said mammal is a human.
 8. A method according toclaim 7 wherein said dosing interval is once-weekly and said unit dosagecomprises about 70 mg of alendronate monosodium trihydrate, on analendronic acid active basis.
 9. A method according to claim 7 whereinsaid dosing interval is twice-weekly and said unit dosage comprisesabout 35 mg of alendronate monosodium trihydrate, on an alendronic acidactive basis.
 10. A method according to claim 7 wherein said dosinginterval is biweekly and said unit dosage comprises about 140 mg ofalendronate monosodium trihydrate, on an alendronic acid active basis.11. A method according to claim 7 wherein said dosing interval istwice-monthly and said unit dosage comprises about 140 mg of alendronatemonosodium trihydrate, on an alendronic acid active basis.
 12. A methodfor preventing osteoporosis in a mammal in need of such treatment, saidmethod comprising orally administering to said mammal a pharmaceuticallyeffective amount of a bisphosphonate as a unit dosage according to acontinuous schedule having a dosing interval selected from the groupconsisting of once-weekly dosing, twice-weekly dosing, biweekly dosing,and twice-monthly dosing.
 13. A method according to claim 12 whereinsaid mammal is a human.
 14. A method according to claim 13 wherein saiddosing interval is once-weekly and said unit dosage comprises about 35mg of alendronate monosodium trihydrate, on an alendronic acid activebasis.
 15. A method according to claim 13 wherein said dosing intervalis twice-weekly and said unit dosage comprises about 17.5 mg ofalendronate monosodium trihydrate, on an alendronic acid active basis.16. A method according to claim 13 wherein said dosing interval isbiweekly and said unit dosage comprises about 70 mg of alendronatemonosodium trihydrate, on an alendronic acid active basis.
 17. A methodaccording to claim 13 wherein said dosing interval is twice-monthly andsaid unit dosage comprises about 70 mg of alendronate monosodiumtrihydrate, on an alendronic acid active basis.
 18. A method fortreating abnormal bone resorption in a human in need of such treatmentcomprising orally administering to said human a unit dosage of abisphosphonate, said unit dosage comprising from about 17.5 mg to about140 mg, on an alendronic acid basis, of a bisphosphonate selected fromthe group consisting of alendronate, pharmaceutically acceptable saltsthereof, and mixtures thereof.
 19. A method according to claim 18wherein said unit dosage comprises about 35 mg of the bisphosphonate.20. A method according to claim 18 wherein said unit dosage comprisesabout 70 mg of the bisphosphonate.
 21. A method according to claim 20wherein said unit dosage is administered once-weekly.
 22. A methodaccording to claim 18 wherein said unit dosage comprises about 140 mg ofthe bisphosphonate.
 23. A method for preventing abnormal bone resorptionin a human in need of such treatment comprising orally administering tosaid human a unit dosage of a bisphosphonate, said unit dosagecomprising from about 8.75 mg to about 70 mg, on an alendronic acidbasis, of a bisphosphonate selected from the group consisting ofalendronate, pharmaceutically acceptable salts thereof, and mixturesthereof, on an alendronic acid active weight basis.
 24. A methodaccording to claim 23 wherein said unit dosage comprises about 17.5 mgof the bisphosphonate.
 25. A method according to claim 23 wherein saidunit dosage comprises about 35 mg of the bisphosphonate.
 26. A methodaccording to claim 25 wherein said unit dosage is administeredonce-weekly.
 27. A method according to claim 23 wherein said unit dosagecomprises about 70 mg of the bisphosphonate.
 28. A method for inhibitingbone resorption in a mammal, said method comprising sequentially orallyadministering to said mammal a pharmaceutically effective amount of aunit dosage of a histamine H2 blocker or a proton pump inhibitor and aunit dosage of a bisphosphonate according to a continuous schedulehaving a dosing interval selected from the group consisting ofonce-weekly dosing, twice-weekly dosing, biweekly dosing, twice-monthlydosing.
 29. A method according to claim 28 wherein said histamine H2blocker or said proton pump inhibitor is administered from about 30minutes to about 24 hours prior to the administration of saidbisphosphonate.
 30. A pharmaceutical composition comprising about 70 mg,on an alendronic acid active basis, of a bisphosphonate selected fromthe group consisting of alendronate, pharmaceutically acceptable saltsthereof, and mixtures thereof.
 31. A pharmaceutical compositioncomprising about 140 mg, on an alendronic acid active basis, of abisphosphonate selected from the group consisting of alendronate,pharmaceutically acceptable salts thereof, and mixtures thereof.
 32. Akit for inhibiting bone resorption in a mammal, said kit comprising atleast one pharmaceutically effective unit dosage of a bisphosphonate fororal administration according to a continuous schedule having a dosinginterval selected from the group consisting of once-weekly dosing,twice-weekly dosing, biweekly dosing, and twice-monthly dosing.
 33. Amethod for inhibiting bone resorption in a mammal, said methodcomprising orally administering to said mammal a pharmaceuticallyeffective amount of a bisphosphonate as a unit dosage according to acontinuous schedule having a periodicity from about once every 3 days toabout once every 16 days.